PROJECT SUMMARY: Brain rhythms arise from the temporal coordination of activity in organized networks of neurons, but the extent to which the rhythmic coordination of spiking activity facilitates information processing in the brain is not well understood. The medial temporal lobe (MTL), a system of interconnected structures important for learning and memory, exhibits highly dynamic rhythms with unique oscillatory frequencies present during distinct behavioral states. Although great advances have been made in describing both single cell and rhythmic correlates of learning and memory in MTL structures, relatively few studies examine the interaction of these phenomena. By studying how MTL cells engage in their surrounding rhythmic circuits during behavior and applying methods to reduce or enhance this engagement, we can ascertain the mechanisms through which rhythmic coordination mediates communication between MTL structures, local information processing within structures, and learning and memory function. The proposed project will examine how rhythmic input from the lateral entorhinal cortex (LEC) influences processing in downstream subregions of the hippocampus and performance in a context-guided odor association task. Through the combined use of large-scale neural recordings and electrical stimulation, this project aims to 1) characterize rhythmic activity in the LEC and each hippocampal subregion during an associative memory task and 2) modify endogenous rhythmic activity in the LEC to test whether rhythmic LEC input is sufficient to engage downstream hippocampal neurons in task- relevant activity that facilitates learning. Using a combination of tetrodes and high-density silicon probes, both single cell and local field potential recordings will be acquired from the LEC as well as the dendritic and somatic layers of the dentate gyrus, CA3, and CA1 subregions of the hippocampus. In Specific Aim 1, cortical and intrinsic hippocampal influences upon rhythmic activity in each subregion will be identified by performing current source density analysis and localizing current sources and sinks to the distal or proximal dendritic regions, respectively. Applied probability models will also be used to determine the extent to which rhythmic dynamics in LEC and each subregion predict the physiological responses of other connected regions. In Specific Aim 2, alternating current stimulation will be used to induce rhythms in the LEC during and odor association task. This aim will test whether rhythmic inputs are sufficient to engage the hippocampus in meaningful rhythmic processing and improve learning. The results of this project will ultimately enable the development of new treatment avenues that target improvements in rhythmic coordination to alleviate memory deficits.